Safe and Targeted Sonodynamic Cancer Therapy Using Biocompatible Exosome-Based Nanosonosensitizers

Sonodynamic therapy (SDT), wherein sonosensitizers irradiated with ultrasound (US) produce cytotoxic reactive oxygen species (ROS), has garnered great attention as a promising alternative to photodynamic therapy owing to the significantly increased depth of tissue penetration. The development of nanocarriers that can selectively deposit sonosensitizers into tumor tissues without systemic toxicity is crucial to facilitate the translation of SDT to clinical use. In this study, exosomes, a class of naturally occurring nanoparticles, were utilized as nanocarriers for safe and cancer-targeted delivery of a sonosensitizer, indocyanine green (ICG). The exosomes were surface-engineered with an active cancer-targeting ligand, folic acid (FA), to increase the cancer specificity of the ICG-loaded exosomes (ExoICG). The FA-conjugated, ICG-loaded exosomes (FA-ExoICG) greatly improved aqueous stability and cellular uptake of ICG, resulting in significantly increased ROS generation in breast cancer cells. As a result, the FA-ExoICG demonstrated greater sonotoxicity against cancer cells than ExoICG and free ICG. The in vivo study revealed that compared to ExoICG, more FA-ExoICG accumulated in tumors, and their pharmacokinetic properties were superior. Notably, tumor growth in mice was significantly suppressed, without systemic toxicity, by a single intravenous injection of the FA-ExoICG and subsequent US irradiation. Therefore, this study demonstrated that active cancer-targeted FA-ExoICG could serve as effective nanosonosensitizers for safe and targeted cancer treatment.